Coronary artery stenosis, resulting in impaired cardiac perfusion, ischemia, and the risk of myocardial infarction, is a major cause of morbidity and mortality in the U. S. population. There is currently tremendous interest in understanding the endogenous responses to ischemia and infarction. These studies may lead to the development of novel therapeutic strategies that protect the heart by promoting adaptive responses or by preventing maladaptive responses. Ischemia is characterized by deprivation of oxygen (hypoxia), metabolic substrates, and cytokines/survival factors, as well as accumulation of toxic metabolites. Despite the complex pathophysiology of ischemia, hypoxia alone is a sufficient stimulus to induce a variety of adaptive responses that protect against ischemia-reperfusion injury. An important mediator of these responses is hypoxia-inducible factor 1 (HIF-1), a transcription factor that regulates the expression of hundreds of genes in response to changes in cellular oxygenation. Among the known HIF-1 target genes are those encoding erythropoietin (EPO) and vascular endothelial growth factor (VEGF), which promote oxygen delivery to tissues by stimulating the production of red blood cells and blood vessels, respectively. HIF-1 target genes also encode survival factors, such as insulin-like growth factor 2 as well as EPO and VEGF, which can block apoptotic signaling induced by ischemia. HIF-1 also controls the expression of glucose transporters and glycolytic enzymes, which are required for anaerobic ATP production. In this proposal, we will investigate the role of HIF-1 and of proteins encoded by HIF-1 target genes, such as EPO, in promoting protection against cardiac ischemia-reperfusion injury. Aim 1 will investigate the mechanisms by which EPO protects the heart from injury following ischemia and reperfusion. Aim 2 will investigate the role of HIF-1 in mediating adaptive responses to cardiac ischemia and reperfusion. Aim 3 will investigate the mechanisms and consequences of the recruitment of bone marrowderived stromal cells to the ischemic heart,